Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study.
Por:
von Hoff K, Haberler C, Schmitt-Hoffner F, Schepke E, de Rojas T, Jacobs S, Zapotocky M, Sumerauer D, Perek-Polnik M, Dufour C, van Vuurden D, Slavc I, Gojo J, Pickles JC, Gerber NU, Massimino M, Gil-da-Costa MJ, Garami M, Kumirova E, Sehested A, Scheie D, Cruz-Martínez O, Moreno L, Cho J, Zeller B, Bovenschen N, Grotzer M, Alderete D, Snuderl M, Zheludkova O, Golanov A, Okonechnikov K, Mynarek M, Juhnke BO, Rutkowski S, Schüller U, Pizer B, Zezschwitz BV, Kwiecien R, Wechsung M, Konietschke F, Hwang EI, Sturm D, Pfister SM, von Deimling A, Rushing EJ, Ryzhova M, Hauser P, Lastowska M, Wesseling P, Giangaspero F, Hawkins C, Figarella-Branger D, Eberhart C, Burger P, Gessi M, Korshunov A, Jacques TS, Capper D, Pietsch T and Kool M
Publicada:
1 sep 2021
Ahead of Print:
2 jun 2021
Resumen:
BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.
Filiaciones:
von Hoff K:
Department of Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany
Haberler C:
Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Austria
Schmitt-Hoffner F:
Hopp Children´s Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
Schepke E:
The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
de Rojas T:
Pediatric OncoGenomics Unit, Children's University Hospital Niño Jesús, Madrid, Spain
Jacobs S:
Department of Pediatrics, KU Leuven and University Hospitals Leuven, Leuven, Belgium
Zapotocky M:
Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Sumerauer D:
Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Perek-Polnik M:
Department of Oncology, The Children's Memorial Health Institute, University of Warsaw, Warsaw, Poland
Dufour C:
Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Villejuif, France
Paris-Saclay University, INSERM, Molecular predictors and New targets in Oncology, Villejuif, France
van Vuurden D:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Slavc I:
Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
Gojo J:
Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
Pickles JC:
Developmental Biology and Cancer Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Gerber NU:
Department of Oncology, University Children's Hospital, Zurich, Switzerland
Massimino M:
Pediatric Unit, Fondazione IRCCS Istituto Nazionale die Tumori, Milan, Italy
Gil-da-Costa MJ:
Pediatric Oncology Department, University Hospital S.João, Porto, Portugal
Garami M:
2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
Kumirova E:
Department of Neuro-Oncology, Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia
Sehested A:
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
Scheie D:
Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Frederik Vs vej 11, 2100 Copenhagen, Denmark
Cruz-Martínez O:
Pediatric Oncology Department. Hospital Sant Joan de Deu. Barcelona, Spain
Moreno L:
Paediatric Haematology & Oncology Division, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Cho J:
Dept. of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
Zeller B:
Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
Bovenschen N:
Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands
Grotzer M:
Department of Oncology, University Children's Hospital, Zurich, Switzerland
Alderete D:
Service of Hematology/Oncology, Hospital JP Garrahan, Buenos Aires, Argentina
Snuderl M:
Department of Pathology, NYU Langone Health and School of Medicine, New York, NY, USA
Zheludkova O:
Department of Neurooncology, Russian Scientific Center of Radiology, Moscow, Russia
Golanov A:
Department of Neuroradiology, Burdenko Neurosurgical Institute, Moscow, Russia
Okonechnikov K:
Hopp Children´s Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Mynarek M:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg
Juhnke BO:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg
Rutkowski S:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg
Schüller U:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Research Institute Children's Cancer Center Hamburg, Hamburg, Germany
Pizer B:
Institute of Translational Research, University of Liverpool, UK
Zezschwitz BV:
Department of Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany
Kwiecien R:
Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany
Wechsung M:
Institute of Biometry and Clinical Epidemiology, Charité University Medicine and Berlin Institute of Health, Berlin, Germany
Konietschke F:
Institute of Biometry and Clinical Epidemiology, Charité University Medicine and Berlin Institute of Health, Berlin, Germany
Hwang EI:
Department of Pediatric Hematology-Oncology, Center for Cancer and Immunology Research and Neuroscience Research, Children's National Medical Center, Washington DC, USA
Sturm D:
Hopp Children´s Cancer Center (KiTZ), Heidelberg, Germany
Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany
Pfister SM:
Hopp Children´s Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany
von Deimling A:
Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Rushing EJ:
Institute of Neuropathology, University Medical Center Zurich, Zurich, Switzerland
Ryzhova M:
Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia
Hauser P:
2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
Lastowska M:
Department of Pathomorphology, Children's Memorial Health Institute, Warsaw, Poland
Wesseling P:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Amsterdam University Medical Center / VUmc, Amsterdam, The Netherlands
Giangaspero F:
Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy
IRCCS Neuromed, Pozzilli (IS), Italy
Hawkins C:
Division of Pathology, The Hospital for Sick Children, Toronto, Canada
Figarella-Branger D:
Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France
Eberhart C:
Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
Burger P:
Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
Gessi M:
Neuropathology Unit, Division of Pathology, Fondazione Policlinico Universitario "A.Gemelli" IRCCS, Università Cattolica S.Cuore, Rome, Italy
Korshunov A:
Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Jacques TS:
Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Capper D:
Department of Neuropathology, Charité University Medicine, and Berlin Institute of Health, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
Pietsch T:
Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, DZNE German Center for Neurodegenerative Diseases, Bonn, Germany
Kool M:
Hopp Children´s Cancer Center (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Green Published
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